Attention-deficit/hyperactivity disorder in pregnancy and the postpartum period.

Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a diagnosis of attention-deficit/hyperactivity disorder. Many women are diagnosed and treated during their reproductive years, which leads to management implications during pregnancy and the postpartum period. We know from clinical practice that attention-deficit/hyperactivity disorder symptoms frequently become challenging to manage during the perinatal period and require additional support and attention. There is often uncertainty among healthcare providers about the management of attention-deficit/hyperactivity disorder in the perinatal period, particularly the safety of pharmacotherapy for the developing fetus. This guideline is focused on best practices in managing attention-deficit/hyperactivity disorder in the perinatal period. We recommend (1) mitigating the risks associated with attention-deficit/hyperactivity disorder that worsen during the perinatal period via individualized treatment planning; (2) providing psychoeducation, self-management strategies or coaching, and psychotherapies; and, for those with moderate or severe attention-deficit/hyperactivity disorder, (3) considering pharmacotherapy for attention-deficit/hyperactivity disorder, which largely has reassuring safety data. Specifically, providers should work collaboratively with patients and their support networks to balance the risks of perinatal attention-deficit/hyperactivity disorder medication with the risks of inadequately treated attention-deficit/hyperactivity disorder during pregnancy. The risks and impacts of attention-deficit/hyperactivity disorder in pregnancy can be successfully managed through preconception counselling and appropriate perinatal planning, management, and support.

Virtual twins for model-informed precision dosing of clozapine in patients with treatment-resistant schizophrenia.

Model-informed precision dosing using virtual twins (MIPD-VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD-VT approach (Simcyp version 21), we predicted the steady-state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment-resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD-VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2 ) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady-state clozapine concentrations were overpredicted two to four-fold. This work supports the application of a high virtualization MIPD-VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug-drug interactions, particularly with fluvoxamine augmentation.

SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases.

OBJECTIVE: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia. METHODS: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described. RESULTS: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations. CONCLUSIONS: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.

A Genetic Counselor's Reflections on Lessons Learned, Challenges, and Successes Experienced during a One-Year Pilot Integration in a Primary Care Clinic.

This practice-related insight article describes the experience of a genetic counselor being integrated into a multidisciplinary primary care clinic that provides care for a predominantly marginalized patient population in Victoria, British Columbia, Canada. Reflections on the lessons learned, including challenges and successes during this 1-year pilot integration are shared by the genetic counselor in the context of exploring the potential value a genetic counselor can provide while embedded in a primary care clinic. The relationship between clinical genetic counseling practice and a culturally safe and trauma-informed approach in primary care is explored, and additional steps are described that can be taken to facilitate more equitable and inclusive access to genetic counseling services for underserved and vulnerable patient populations.

Reflections of parents of children with 22q11.2 Deletion Syndrome on the experience of receiving psychiatric genetic counseling: 'Awareness to Act'.

Individuals with 22q11.2 deletion syndrome (22qDS) have a 25%-41% risk for a psychotic disorder. Although early intervention for psychiatric conditions leads to the best long-term outcomes, healthcare providers often provide inadequate information about these issues and psychiatric services are underused by this population. We conducted semi-structured interviews with parents of children with 22qDS a month after they received psychiatric genetic counseling (pGC), to evaluate outcomes and perceived value of pGC with respect to parents' needs. Using grounded theory, we generated a theoretical framework of the process of building parental awareness of psychiatric risks associated with 22qDS and protective and management strategies for mental health (MH). Parents described how after their child's diagnosis with 22qDS, a variety of barriers stalled their building awareness of psychiatric risk and protective/management strategies: dealing with the immediate symptoms of 22qDS; child's young age; parental fear and stigma; and missing MH guidance. These barriers led them to carry the burden of worrying over missing emerging psychiatric symptoms and the stress over advocating for their child's MH. Parents indicated pGC was beneficial in that led them to achieve an 'awareness to act,' feeling confident in being alert and equipped to protect and/or manage their child's MH.

A cross-sectional study of the relationship between CYP2D6 and CYP2C19 variations and depression symptoms, for women taking SSRIs during pregnancy.

Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical guidelines provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; however, they are based on evidence from non-pregnant cohorts. This study aimed to test the hypothesis that women with function-altering variants (increased, decreased, or no function) in these pharmacogenes, taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants are associated with normal SSRI metabolism. Comprehensive CYP2D6 and CYP2C19 genotyping using a range of methods, including gene copy number analysis, was performed as secondary analyses on two longitudinal cohorts of pregnant women (N = 83) taking the SSRIs paroxetine, citalopram, escitalopram, or sertraline. The Kruskal-Wallis test compared mean depression scores across four predicted metabolizer groups: poor (n = 5), intermediate (n = 10), normal (n = 53), and ultrarapid (n = 15). There were no significant differences between mean depression scores across the four metabolizer groups (H(3) = .73, p = .87, eta-squared = .029, epsilon-squared = .0089). This is the first study of the relationship in pregnancy between CYP2C19 pharmacogenetic variations and depression symptoms in the context of SSRI use. Findings from this initial study do not support the clinical use of pharmacogenetic testing for SSRI use during the second or third trimesters of pregnancy, but these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, especially as companies offering direct-to-consumer genetic testing expand their marketing efforts.

Genetic counseling research and COVID-19: A lesson in resiliency.

GenCOUNSEL is the largest genetic counseling research grant awarded to date and brings together experts in genetic counseling, genomics, law and policy, health services implementation, and health economics research. It is the first project of its kind to examine the genetic counseling issues associated with the clinical implementation of genome-wide sequencing (exome and genome sequencing). GenCOUNSEL is a Canadian-based, multi-method research study that takes place over a variety of sites, including non-clinical, clinical, and laboratory research sites and includes the training of undergraduate and graduate students. The COVID-19 pandemic will likely have a lasting impact on genetic counseling service delivery, research, and training. Almost every aspect of the GenCOUNSEL research project has been impacted by the COVID-19 pandemic. Here we describe how our research recruitment strategies, methods, resource allocation, and training capacity have been affected. We discuss ways that we have adapted to the pandemic including revision of our research methods and work to understand the barriers in order to optimize opportunities. We finish with take-home messages to fellow researchers highlighting the importance of resiliency in genetic counseling research.

Psychiatric genetic counseling for serious mental illness: Impact on psychopathology and psychotropic medication adherence.

For people with serious mental illness (SMI) (schizophrenia, bipolar disorder, schizoaffective disorder), psychiatric genetic counseling (PGC) has been shown to significantly increase empowerment and illness management self-efficacy. While these outcomes are important, they are also theoretical precursors for behavior changes (e.g. improved medication adherence), and improved mental health. Therefore, we conducted the first study (repeated-measures/within-subjects design) to test the hypothesis that PGC would reduce psychiatric symptoms due to increased medication adherence. Between 2013-2018, we recruited N = 109 individuals (age 19-72) with SMI and administered the short Positive and Negative Syndrome Scale (short-PANSS) and Brief Adherence Rating Scale (BARS) at four timepoints; twice Pre-PGC (T1: 1-month Pre-PGC and T2: immediately Pre-PGC), to assess change in adherence/symptoms without any intervention (internal control condition), and twice Post-PGC (T3: 1-month and T4: 2-months Post-PGC), to assess impact of PGC. A quantile regression model investigated the relationships between short-PANSS, timepoints, and BARS. There was a significant relationship between short-PANSS and timepoints at the 75th (T4 short-PANSS scores < T1 and T2) and 90th quantiles (T4 short-PANSS scores < T2), but these results were not explained by improved medication adherence. PGC for SMI may reduce psychiatric symptoms, but confirmatory work and studies to examine mechanism are needed.

A prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk women.

BACKGROUND: The etiology of postpartum psychopathologies are not well understood, but folate metabolism pathways are of potential interest. Demands for folate increase dramatically during pregnancy, low folate level has been associated with psychiatric disorders, and supplementation may improve symptomatology. The MTHFR C677T variant influences folate metabolism and has been implicated in depression during pregnancy. OBJECTIVE: To conduct a prospective longitudinal study to explore the relationship between MTHFR C677T genotype, folate levels, and postpartum psychopathology in at-risk women. HYPOTHESIS: In the first three months postpartum, folate will moderate a relationship between MTHFR genotype and depression, with TT homozygous women having more symptoms than CC homozygous women. METHODS: We recruited 365 pregnant women with a history of mood or psychotic disorder, and at 3 postpartum timepoints, administered the Edinburgh Postnatal Depression Scale (EPDS); Clinician-Administered Rating Scale for Mania (CARS-M) and the Positive and Negative Symptom Scale (PANSS) and drew blood for genotype/folate level analysis. We used robust linear regression to investigate interactions between genotype and folate level on the highest EPDS and CARS-M scores, and logistic regression to explore interactions with PANSS psychosis scores above/below cut-off. RESULTS: There was no significant interaction effect between MTHFR genotype and folate level on highest EPDS (p = 0.36), but there was a significant interaction between genotype, folate level and log(CARS-M) (p = 0.02); post-hoc analyses revealed differences in the effect of folate level between CC/CT, and TT genotypes, with folate level in CC and CT having an inverse relationship with symptoms of mania, while there was no relationship in participants with TT genotype. There was no significant interaction between MTHFR genotype and folate level on the likelihood of meeting positive symptom criteria for psychosis on the PANSS (p = 0.86). DISCUSSION: These data suggest that perhaps there is a relationship between MTHFR C677T, folate level and some symptoms of postpartum psychopathology.

Preliminary examination of the validity of the NIH toolbox cognition battery in treatment-resistant psychosis.

Objective: Prior research has suggested that treatment-resistant psychosis (TRP) may be a categorically distinct subtype from treatment-responsive psychotic disorders. However, relatively few studies have investigated the cognitive profile of individuals with TRP. Moreover, no prior studies have investigated the effectiveness of using the NIH Toolbox Cognition Battery (NTCB) for assessing cognition among psychiatric inpatients despite its promising efficiency and practicality in such settings. The current study aimed to investigate the validity of the NTCB and the associated cognitive profile of inpatients with TRP.Methods: Participants (N = 38) were administered the NTCB and a neuropsychological test battery. The Positive and Negative Syndrome Scale and the Routine Assessment of Patient Progress measured psychosis symptomatology and daily functioning, respectively.Results: Results showed deficits relative to normative values in fluid cognitive abilities using the NTCB, as predicted. There was strong convergent validity and adequate divergent validity between the NTCB subtests and corresponding neuropsychological measures, though no NTCB subtest correlated with performance on the Wisconsin Card Sorting Task. NTCB performance correlated with positive and disorganized symptoms of psychosis as well as daily functioning.Conclusions: Taken together, the NTCB appears to be a relatively strong tool for cognitive screening among psychiatric inpatients and may be used to identify which patients might benefit from further neuropsychological evaluation.

A Matched Cohort Study of Postpartum Placentophagy in Women With a History of Mood Disorders: No Evidence for Impact on Mood, Energy, Vitamin B12 Levels, or Lactation.

OBJECTIVE: Although empirical studies investigating its effects are scarce, postpartum placentophagy is increasing in popularity because of purported benefits on mood, energy, lactation, and overall nutrition. Therefore, this study sought to test the hypotheses that women who consumed their placenta (placentophagy exposed [PE]) would have (1) fewer depressive symptoms, (2) more energy, (3) higher vitamin B12 levels, and (4) less pharmaceutical lactation support during the postpartum than women who did not consume their placenta (non-placentophagy exposed [NE]). METHODS: Using data from a large, longitudinal study of gene × environment effects involving perinatal women with a history of mood disorders, the study investigators identified a PE cohort and matched them 4:1 (by psychiatric diagnosis, psychotropic medication use, supplementation, income, and age) with an NE cohort from the same dataset. The study investigated differences between the PE and NE cohorts with respect to scores on the Edinburgh Postnatal Depression Scale and Sleep-Wake Activity Inventory, vitamin B12 levels, and the use of pharmaceutical lactation support (Canadian Taskforce Classification II-2). RESULTS: The sample of 138 women (28 in the PE cohort, matched to 110 in the NE cohort) provided 80% power at α = 0.0125 to detect an effect of moderate magnitude (which can be used to approximate an effect of clinically significant magnitude).There were no differences in Edinburgh Postnatal Depression Scaleor Sleep-Wake Activity Inventory scales (P = 0.28 and P = 0.39, respectively), vitamin B12 levels (P = 0.68), or domperidone use (P = 1) between the PE and NE cohorts. CONCLUSION: These data provide no support for the idea that postpartum placentophagy improves mood, energy, lactation, or plasma vitamin B12 levels in women with a history of mood disorders.

Short interpregnancy intervals, maternal folate levels, and infants born small for gestational age: a preliminary study in a Canadian supplement-using population.

Short interpregnancy intervals (SIPI) have been associated with increased risks for adverse neonatal outcomes including preterm delivery and infants small for gestational age (SGA). It has been suggested that mechanistically, adverse neonatal outcomes after SIPI arise due to insufficient recovery of depleted maternal folate levels prior to the second pregnancy. However, empirical data are lacking regarding physiological folate levels in pregnant women with SIPI and relationships between quantified physiological folate levels and outcomes like SGA. Therefore, we sought to test 2 hypotheses, specifically that compared with controls women with SIPI would: (i) have lower red blood cell folate (RBCF) levels and (ii) be more likely to have SGA infants (defined as <10th percentile). Using data collected in British Columbia, Canada, for a larger study on perinatal psychopathology, we documented supplementation use and compared prenatal RBCF levels and proportion of SGA infants between women with SIPI (second child conceived ≤24 months after previous birth, n = 26) and matched controls (no previous pregnancies, or >24 months between pregnancies, n = 52). There were no significant differences in either mean RBCF levels (Welch's t test, p = 0.7) or proportion of SGA infants (Fisher's exact test, p = 0.7) between women with SIPI and matched controls. We report the first data about RBCF levels in the context of SIPI. If confirmed, our finding of no relationship between these variables in this population suggests that continued folic acid supplementation following an initial pregnancy mitigates folate depletion. We found no relationship between SIPI and SGA.

Perinatal psychosis in mothers with a history of major depressive disorder.

While women with a history of major depressive disorder (MDD) have higher chances for postpartum depressive and manic episodes, little is known about their chance for postpartum psychosis (PPP). We prospectively assessed the frequency of perinatal psychotic symptoms among primiparous women with a history of MDD only (structured clinical interview was used to exclude women with pre-existing histories of mania or psychosis) and explored whether sex of the baby influenced these symptoms.The presence of symptoms of psychosis was defined using previously established cutoff scores on five key items from the Positive and Negative Syndrome Scale (PANSS), which was administered during pregnancy, at 1 week, 1 month, and 3 months postpartum.Fourteen of 60 women (23%) scored above threshold for psychosis at one or more time points, with 6 experiencing postpartum onset. There was a non-significant trend (p = 0.073) towards higher frequency of these symptoms among mothers of girls.If controlled studies using diagnostic interviews confirm that psychotic symptoms are relatively common among women with MDD, monitoring for psychosis during the perinatal period may be indicated in this population. The potential effect of sex of the baby on mothers' chance for PPP requires further study.

Parents' experiences of receiving their child's genetic diagnosis: a qualitative study to inform clinical genetics practice.

Little is currently known about how parents experience the medical genetics appointment at which their child receives a genetic diagnosis. We conducted semi-structured in-person interviews with 13 parents of 10 index children to explore their experience in the medical genetics appointment in which they received their child's genetic diagnosis. Guided by grounded theory, we used a constant comparative approach to data analysis. Transcribed interviews were coded and sorted, and thematic categories identified. Sixty-one and a half percent of parents experienced the diagnosis session as negative, 23% felt the experience was positive, and 15.5% were ambivalent. Receiving emotional support, an outline of the follow-up plans, and messages of hope and perspective during the session seemed to positively influence parents' experience, while feeling that their role was as a passive receiver of information and the use of difficult medical terminology negatively influenced parents' overall experience. Parental preparedness for the information, and the parents' emotional reaction to the diagnosis were also factors that influenced the parental experience. Few participants understood the role of the genetic counselor. Our results provide in-depth insight into the parental experience of the pediatric medical genetics diagnosis session. We propose a mechanism through which parental experience shapes their perception of the medical genetics session.

Mania and depression in the perinatal period among women with a history of major depressive disorders.

Women with a history of major depressive disorder (MDD) have increased risks for postpartum depression, but less is known about postpartum mania in this population. The objectives of this study were to prospectively determine the frequency with which mania occurs in the postpartum among women who have a history of MDD and to explore temporal relationships between onset of mania/hypomania and depression. We administered the Structured Clinical Interview for DSM IV disorders (SCID) to pregnant women with a self-reported history of MDD to confirm diagnosis and exclude women with any history of mania/hypomania. Participants completed the Edinburgh Postnatal Depression Scale and Altman Self-Rating Mania Scale (ASRM) once during the pregnancy (∼26 weeks) and 1 week, 1 month, and 3 months postpartum. Among women (n = 107) with a SCID-confirmed diagnosis of MDD, 34.6 % (n = 37) experienced mania/hypomania (defined by an ASRM score of ≥6) at ≥1 time point during the postpartum, and for just over half (20/37, 54 %), onset was during the postpartum. The highest frequency of mania/hypomania (26.4 %, n = 26) was at 1 week postpartum. Women who experienced mania/hypomania at 1 week postpartum had significantly more symptoms of mania/hypomania later in the postpartum. A substantive proportion of women with a history of MDD may experience first onset of mania/hypomania symptoms in the early postpartum, others may experience first onset during pregnancy. Taken with other recent data, these findings suggest a possible rationale for screening women with a history of MDD for mania/hypomania during the early postpartum period, but issues with screening instruments are discussed.

Awareness of genetic counseling and perceptions of its purpose: a survey of the Canadian public.

Genetic counseling can result in better outcomes when clients understand what to expect, and at least theoretically, at some point in their lifespan, anyone could be referred for or benefit from genetic counseling. Thus, in order to identify (and ultimately address) issues around awareness of genetic counseling and perceptions of its purpose, we surveyed the Canadian general population. We acquired 1,000 telephone numbers corresponding to a demographically representative sample of Canada from Survey Sampling International, and invited individuals to participate in a telephone-based survey. We administered a purpose-designed survey (in either French or English) comprising questions regarding: demographics, whether or not the individual had heard of genetic counseling, and 15 Likert scale-rated (strongly disagree-strongly agree) items about the possible purposes of genetic counseling. Responses to these 15 items were used to generate a total "knowledge score". Of the 1,000 numbers, n = 372 could not be reached, and the survey was successfully administered to n = 188 individuals (response rate 30 %). Most respondents (n = 129, 69 %) had not heard of genetic counseling, and substantial proportions thought that genetic counseling aims to prevent genetic diseases and abnormalities, help couples have children with desirable characteristics, and help people to understand their ancestry. These data could be used to inform the strategy for development of future awareness efforts, and as a baseline from which to measure their effects.

Red blood cell folate levels in pregnant women with a history of mood disorders: a case series.

BACKGROUND: Maternal folate supplementation reduces offspring risk for neural tube defects (NTDs) and other congenital abnormalities. Maternal red blood cell (RBC) folate concentrations of >906 nmol/L have been associated with the lowest risk of having a neural tube defect affected pregnancy. Mood disorders (e.g., depression, bipolar disorder) are common among women and can be associated with folate deficiency. Thus, pregnant women with histories of mood disorders may be prone to RBC folate levels insufficient to provide optimal protection against neural tube defects. Although previous studies have assessed RBC folate concentrations in pregnant women from the general population, none have looked specifically at a group of pregnant women who have a history of a mood disorder. METHODS: We collected data about RBC folate concentrations and folic acid supplement intake during early pregnancy (<161 days gestation) from n = 24 women with histories of mood disorders. We also collected information about offspring congenital abnormalities and birth weight. RESULTS: Among women with histories of mood disorders, the mean RBC folate concentration was 674 nmol/L (range, 362-1105 nmol/L). Only 12.5% (n = 3) of the women had RBC folate concentrations >906 nmol/L, despite all participants reporting current daily use of folic acid supplements. Data regarding offspring were available for 22 women: birth weights ranged from 2296 g to 4819 g, and congenital abnormalities were identified in two (hypoplastic left heart, annular pancreas). CONCLUSION: Data from this exploratory case series suggest a need for future larger scale controlled studies investigating RBC folate concentrations in early pregnancy and offspring outcomes among women with and without histories of mood disorders.

Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism.

Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome.